以CCR5为靶点的小分子抗艾滋病药物的研究与开发

综述趋化因子受体5 (CCR5 )拮抗剂的作用机制,介绍若干具代表性的小分子CCR5拮抗剂,并探讨其构效关系。CCR5属于G蛋白偶联受体超家族,是HIV- 1入侵机体细胞的主要辅助受体之一。以CCR5为为靶点的小分子抗艾滋病药物的研究与开发备受关注。     

CCR5小分子拮抗剂类抗艾滋病药物研究进展

趋化因子受体CCR5是抗艾滋病药物作用的重要靶点之一。目前，已经开发了许多活性强、选择性高的CCR5拮抗剂，其中一部分已进入临床试验阶段。本文对近年来文献报道的CCR5小分子拮抗剂进行综述。     

小分子趋化因子受体4拮抗剂研究进展

CC类人类趋化因子受体4(CCR4)是趋化因子家族中具有7个跨膜结构的G蛋白偶联受体。CCR4受体与自身免疫性疾病、哮喘、特应性皮炎等多种疾病的形成和发展有关,可成为这些疾病新的治疗靶点,受到越来越多学者的关注。CCR4拮抗剂的研究成为研发治疗上述疾病药物新热点。本文对近年来小分子CCR4拮抗剂的研究进展进行综述。     

补体C5a、C5a受体及其拮抗剂的研究进展

C5a是最重要的补体活化产物之一,它与相应的C5a受体结合被激活后,参与了多种疾病的病理过程,如急性肺损伤、脓毒血症、类风湿性关节炎、肾小球肾炎等疾病。如何阻断C5a信号的下传,从而减轻炎症反应一直是免疫学研究的热点问题。目前C5a和C5a受体的拮抗剂主要分为抗C5a抗体、小分子拮抗剂、C5a反义肽、C5a突变体和细菌来源的趋化抑制蛋白等。本文着重介绍C5a和C5a受体的结构与功能,以及相关拮抗剂的研究进展。     

HIV-共受体CCR5的三维结构及与其拮抗剂TAK 779相互作用的比较分子模拟(英文)

目的:研究HIV-1的共受体CCR5与其拮抗剂TAK779的相互作用机制。方法:用比较分子模拟方法建立CCR5受体的三维结构模型;通过量子化学计算得到TAK779分子的结构参数和最优几何构型;用DOCK4.0程序将TAJ779分子对接到CCR5受体的结合位点上。结果:通过分子力学优化得到了CCR5受体的三维结构模型,配体的结合口袋位于第三、五、六、七跨膜区,组成结合口袋的氨基酸残基主要为Thr105、Leu107、Tyr108、Gly111、Phe112、Ser114、Gly115、Lys197、Glu283、Gly286、Met287、Cys290;TAK779与CCR5受体的相互作用方式为氢键、静电和疏水作用;配体与受体的结合能为-51.606 kcal/mol。结论:上述模型有助于进一步理解膜受体识别HIV-1病毒的分子机制并设计新的HIV-1抑制剂。     

抗HIV药物靶点CCR5及HIV对CCR5抑制剂的抗性

趋化因子受体CCR5是细胞膜表面G蛋白偶联受体中的一员.HIV-1在体内与细胞融合时需要CCR5作为辅助受体介导.因此,CCR5可作为抗HIV-1药物的筛选靶点,目前已筛选出多种CCR5抑制剂.但随着CCR5抑制剂的使用,HIV-1对于这些抑制剂的抗性也逐渐产生,而抗性的产生机制还不明确.本文主要介绍CCR5介导HIV-1与细胞融合的机制及HIV-1对CCR5抑制剂的抗性产生机制.     

CCR5阻滞剂马拉韦罗的药理与临床评价

马拉韦罗是一种选择性、可逆的小分子抑制剂,能与细胞膜表面人化学趋化因子受体-5(CCR5)和HIV-1gp120相互作用,抑制CCR5-tropic HIV-1病毒进入细胞,是一种很有前途的新型抗病毒药.现对其药理作用、药动学、药物相互作用及对仅感染CCR5-tropic HIV-1的成年患者的疗效和安全性进行了综述.     

单克隆抗体HIV进入抑制剂PRO140

HIV病毒株可分为R5嗜性和X4嗜性,它们分别通过趋化因子CCR5和CXCR4辅助受体进入CD4细胞。在HIV的整个发展进程中,可常发生其病毒株由R5嗜性转型为X4嗜性,且也有可能某个体同时被R5嗜性和X4嗜性病毒感染,而CCR5拮抗剂则对x4嗜性病毒无效。由Progenics制药公司开发的用于治疗HIV感染的人源化单克隆抗体CCR5拮抗剂PRO140为一种新型HIV进人抑制剂,可与CCR5受体的特殊区段紧密结合,对CCR5产生拮抗作用,从而抑制HIV通过这一辅助受体进入靶细胞;     

小分子CCR5抑制剂的研究进展

在发达国家,高活性抗逆转录病毒疗法(HAART)在控制艾滋病流行方面起了重要的作用[1],但它的治疗方案复杂,费用昂贵,再加上抗药性HIV-1病毒变体的出现以及药物本身的副作用,使得其治疗艾滋病越来越受到限制[2].CCR5辅助受体的发现不仅阐明HIV-1病毒侵入细胞的复杂机制,同时为开发新型抗病毒药物阻断病毒侵入细胞的新治疗方案提供了理论基础.本文就阻断HIV-1感染的小分子CCR5抑制剂的研究进展报道如下.     

毛细管区带电泳研究化合物S009和CC趋化因子受体4三个胞外区相互作用

CC趋化因子受体4（CCR4）是G蛋白偶联受体的一种,在过敏性炎症中起着举足轻重的作用。在本研究中,我们合成了CCR4的三个胞外loop区（EL1–EL3）,用毛细管区带电泳（CZE）的方法研究化合物S009和3个胞外loop区的相互作用。分别进行了定性和定量研究。实验数据表明,化合物S009和EL3有相互作用并通过Scatchard方程计算得到化合物S009和EL3之间的结合常数为（12.5±0.19）×104 M–1。我们的研究确证了CCR4结合小分子的具体胞外域并为进一步发现新型CCR4拮抗剂提供了有帮助的信息。     

CCR3 antagonists: a survey of the patent literature

Background: Since the mid-1990s, there has been significant effort invested in the discovery and clinical development of CC chemokine receptor-3 (CCR3) antagonists as potential therapeutics for airway disease. Objectives/methods: A patent literature review is presented of small molecule CCR3 antagonists comprising the years 2004 to the present. The patent searches were conducted using Derwent Discovery (World patent index) and PCT publication databases. Results/conclusion: At least two small molecule compounds have been reported to advance into clinical trials. However, data that support a definitive proof-of-concept in humans have yet to be disclosed. Nevertheless, patents from various pharmaceutical companies have continued to emerge, revealing diverse chemical classes of potent CCR3 antagonists and reflecting a continued broad interest in this area.     

Chemokine CCR3 antagonists

Because CC chemokine receptor 3 (CCR3) expression is confined to eosinophils, and such leukocytes play an important role in allergic disorders, identification of CCR3 antagonists represents a logical approach to identifying new treatments for eosinophil-associated inflammatory disorders such as asthma. CCR3 is also expressed on basophils, mast cells, airway epithelial cells and a subpopulation of T-helper 2 lymphocytes, which has increased interest in its possible role in allergy. Substantial research efforts by a number of drug companies have been directed at the development of small molecule CCR3 antagonists. This review encompasses patent applications pertaining to disclosures of CCR3 antagonists.     

Oral CCR5 inhibitors: will they make it through?

The therapeutic armamentarium against HIV has recently gained a drug belonging to a novel class of antiretrovirals, the entry inhibitors. The last decade has driven an in-depth knowledge of the HIV entry process, unravelling the multiple engagements of the HIV envelope proteins with the cellular receptorial complex that is composed of a primary receptor (CD4) and a co-receptor (CCR5 or CXCR4). The vast majority of HIV-infected subjects exhibit biological viral variants that use CCR5 as a co-receptor. Individuals with a mutated CCR5 gene, both homo- and heterozygotes, appear to be healthy. For these and other reasons, CCR5 represents an appealing target for treatment intervention, although certain challenges can not be ignored. Promising small-molecule, orally bioavailable CCR5 antagonists are under development for the treatment of HIV-1 infection.     

A novel template for non-peptide CCR5 receptor antagonists

Potent non-peptide chemokine CCR5 receptor antagonists have been identified, based upon a 1(1-aroylpiperidin-4-yl)piperidine template previously employed in a series of muscarinic M₂ receptor antagonists. Two applications claim piperidinylpiperidine and piperidinylpiperazine derivatives, respectively, including compounds with low nanomolar affinity for the CCR5 receptor. Such compounds are claimed to be useful in the treatment of HIV infection and inflammatory diseases.     

CCR5 receptor antagonists in preclinical to phase II clinical development for treatment of HIV

Introduction: The chemokine receptor CCR5 has garnered significant attention in recent years as a target to treat HIV infection largely due to the approval and success of the drug Maraviroc. The side effects and inefficiencies with other first generation agents led to failed clinical trials, prompting the development of newer CCR5 antagonists.

Areas covered: This review aims to survey the current status of ‘next generation’ CCR5 antagonists in the preclinical pipeline with an emphasis on emerging agents for the treatment of HIV infection. These efforts have culminated in the identification of advanced second-generation agents to reach the clinic and the dual CCR5/CCR2 antagonist Cenicriviroc as the most advanced currently in phase II clinical studies.

Expert opinion: The clinical success of CCR5 inhibitors for treatment of HIV infection has rested largely on studies of Maraviroc and a second-generation dual CCR5/CCR2 antagonist Cenicriviroc. Although research efforts identified several promising preclinical candidates, these were dropped during early clinical studies. Despite patient access to Maraviroc, there is insufficient enthusiasm surrounding its use as front-line therapy for treatment of HIV. The non-HIV infection related development activities for Maraviroc and Cenicriviroc may help drive future interests.     

Small molecule HIV entry inhibitors: Part I. Chemokine receptor antagonists: 2004 - 2010

INTRODUCTION: HIV/AIDS is one of the most devastating diseases in the world affecting > 40 million people worldwide. Morbidity and mortality from AIDS are significantly reduced due to the advent of highly active antiretroviral therapy (HAART). Long-term toxicity, emergence of drug resistant HIV strains and drug-drug interactions limit the effectiveness of HAART therapy. Chemokine receptor antagonists can provide drugs with lesser side effects and enhanced anti-HIV activity. Maraviroc, a chemokine co-receptor 5 (CCR5) antagonist from Pfizer, is already in clinical use. AREAS COVERED: This review covers patents and patent applications for small molecule CCR5 and CXC chemokine receptor 4 (CXCR4) antagonists published between 2004 and 2010 and related literature with a focus on recent developments based on lead generation and lead modification. The reader will gain information about the development of small molecule CCR5 and CXCR4 antagonists from the major pharmaceutical and biopharmaceutical companies. EXPERT OPINION: Several small lead molecules (CCR5 and CXCR4 antagonists) have been modified over this period for enhanced therapeutic activity and to obtain drug-like properties. CCR5 antagonists such as TBK-652 and TBK-220 from Tobira Therapeutics, and vicriviroc from Schering Plough showed a lot of promise in the developmental stage.     

Effect of CCR5 receptor antagonists on endocytosis of the human CCR5 receptor in CHO-K1 cells

Background and purpose:

The CCR5 chemokine receptor is a member of the G protein-coupled receptor (GPCR) family that is expressed by macrophages, memory T-lymphocytes and dendritic cells and is activated by chemotactic proteins (e.g. MIP-1α [CCL3], MIP-1β [CCL4] and RANTES [CCL5]). CCR5 is also the principal co-receptor for macrophage-tropic strains of human immunodeficiency virus-1 (HIV-1) and some chemokines can inhibit HIV-1 infection by stimulating CCR5 receptor endocytosis. The aim of this study was to evaluate the effect of CCR5 antagonists on CCR5 endocytosis.

Experimental approach:

The effects of CCR5 agonists and antagonists on receptor internalization in CHO cells, expressing a C-terminal green fluorescent protein-tagged human CCR5 receptor (CCR5-GFP), were quantified using a confocal imaging plate reader.

Key results:

MIP-1α [CCL3], MIP-1β [CCL4] and RANTES [CCL5] were all able to stimulate potently the internalization of CCR5-GFP. This effect was inhibited by the non-peptide antagonist TAK 779. The CCR5 peptide antagonist met-RANTES antagonized MIP-1α-mediated increases in intracellular free calcium but was also able to stimulate a substantial internalization of the human CCR5-GFP receptor. However, CHO cells exhibited an aminopeptidase activity that was able to metabolize sufficient met-RANTES into an agonist metabolite capable of stimulating calcium mobilization via CCR5 receptors in naïve cells.

Conclusions and implications:

These data suggest that there is an endogenous aminopeptidase activity on the surface of CHO cells, that produces a slow internalization of the receptor following a time-dependent conversion of receptor-bound met-RANTES from a CCR5 receptor antagonist into a CCR5 agonist molecule.     

Comparison of the beneficial effects of RS504393, maraviroc and cenicriviroc on neuropathic pain-related symptoms in rodents: behavioral and biochemical analyses

The latest research highlights the role of chemokine signaling pathways in the development of nerve injury-induced pain. Recent studies have provided evidence for the involvement of CCR2 and CCR5 in the pathomechanism underlying neuropathy. Thus, the aim of our study was to compare the effects of a selective CCR2 antagonist (RS504393), selective CCR5 antagonist (maraviroc) and dual CCR2/CCR5 antagonist (cenicriviroc) and determine whether the simultaneous blockade of both receptors is better than blocking only one of them selectively. All experiments were performed using Wistar rats/Swiss albino mice subjected to chronic constriction injury (CCI) of the sciatic nerve. To assess pain-related reactions, the von Frey and cold plate tests were used. The mRNA analysis was performed using RT-qPCR. We demonstrated that repeated intrathecal administration of the examined antagonists attenuated neuropathic pain in rats 7 days post-CCI. mRNA analysis showed that RS504393 did not modulate the spinal expression of the examined chemokines, whereas maraviroc reduced the CCI-induced elevation of CCL4 level. Cenicriviroc significantly lowered the spinal levels of CCL2-4 and CCL7. At the dorsal root ganglia, strong impacts of RS504393 and cenicriviroc on chemokine expression were observed; both reduced the CCI-induced elevation of CCL2-5 and CCL7 levels, whereas maraviroc decreased only the CCL5 level. Importantly, we demonstrated that a single intrathecal/intraperitoneal injection of cenicriviroc had greater analgesic properties than RS504393 or maraviroc in neuropathic mice. Additionally, we demonstrated that cenicriviroc enhanced opioid-induced analgesia. Based on our results, we suggest that targeting CCR2 and CCR5 simultaneously, is an interesting alternative for neuropathic pain pharmacotherapy.     

Chemokine receptor CCR5: from AIDS to atherosclerosis

There is increasing recognition of an important contribution of chemokines and their receptors in the pathology of atherosclerosis and related cardiovascular disease. The chemokine receptor CCR5 was initially known for its role as a co-receptor for HIV infection of macrophages and is the target of the recently approved CCR5 antagonist maraviroc. However, evidence is now emerging supporting a role for CCR5 and its ligands CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) in the initiation and progression of atherosclerosis. Specifically, the CCR5 deletion polymorphism CCR5delta32, which confers resistance to HIV infection, has been associated with a reduced risk of cardiovascular disease and both CCR5 antagonism and gene deletion reduce atherosclerosis in mouse models of the disease. Antagonism of CCL5 has also been shown to reduce atherosclerotic burden in these animal models. Crucially, CCR5 and its ligands CCL3, CCL4 and CCL5 have been identified in human and mouse vasculature and have been detected in human atherosclerotic plaque. Not unexpectedly, CC chemokines have also been linked to saphenous vein graft disease, which shares similarity to native vessel atherosclerosis. Distinct roles for chemokine-receptor systems in atherogenesis have been proposed, with CCR5 likely to be critical in recruitment of monocytes to developing plaques. With an increased burden of cardiovascular disease observed in HIV-infected individuals, the potential cardiovascular-protective effects of drugs that target the CCR5 receptor warrant greater attention. The availability of clinically validated antagonists such as maraviroc currently provides an advantage for targeting of CCR5 over other chemokine receptors.